US6780968B1

US6780968B1 - Monocyclic compounds with four bifunctional residues having NK-2 antagonist action

Info

Publication number: US6780968B1
Application number: US09/355,210
Authority: US
Inventors: Raffaello Giorgi; Cristina Di Bugno; Danilo Giannotti; Carlo Alberto Maggi
Original assignee: Menarini Ricerche SpA
Current assignee: Menarini Ricerche SpA
Priority date: 1997-02-07
Filing date: 1998-02-04
Publication date: 2004-08-24
Anticipated expiration: 2018-02-04
Also published as: JP2001511167A; EP1017711A2; WO1998034949A3; ATE245658T1; ITFI970020A1; CN1246866A; WO1998034949A2; DE69816633D1; IT1291776B1; AR011789A1; MY117392A; ITFI970020A0; DE69816633T2; ES2203934T3; ZA98931B; CA2280228A1; CN1227261C; AU6620198A; EP1017711B1

Abstract

Disclosed are monocyclic compounds containing four bifunctional residues linked together via peptide or pseudopeptide bonds of the general formula (I):having tachykinin receptor antagonist activity. In particular, compounds of formula I are shown to be neurokinin-2 (NK-2) antagonists useful in the treatment or prevention of disorders of the central nervous system, inflammatory diseases, asthma, or pain.

Description

BACKGROUND OF THE INVENTION

The present invention refers to new compounds having the general formula (I):

in which:

X₁, X₂, X₃, X₄, which may be the same or different from one another, represent a group chosen from among —CONR—, —NRCO—, —OCO—, —COO—, —CH₂NR—, —NR—CH₂—, CH₂—CH₂, where R is H or a C_1-3alkyl or benzyl;

f, g, h, m, which may be the same or different from one another, represent a number chosen from among 0, 1 or 2;

R₁and R₂, which may be the same or different from one another, represent a —(CH₂)_r—Ar group, where r=0, 1, 2 and where Ar is an aromatic group chosen from among: benzene, naphthalene, thiophene, benzothiophene, pyridine, quinoline, indole, furan, benzofuran, thiazole, benzothiazole, imidazole, and benzo-imidazole, the said Ar group being possibly substituted with a maximum of 2 residues chosen from among C_1-3alkyl or halo-alkyl, C_1-3alkoxyl, C_2-4amino-alkoxyl, halogen, OH, NH₂, NR₁₃R₁₄where R₁₃and R₁₄, which may be the same or different from one another, represent hydrogen or C_1-3alkyl;

R₃represents a group chosen from among:

hydrogen

linear or branched alkyl having the formula C_nH_2n+1, with n=1-5, cyclo-alkyl or alkylcyclo-alkyl groups having the formula C_nH_2n−1with n=5-9

(CH₂)_r—Ar₁, where r=0, 1, 2 and where Ar₁is an aromatic group chosen from among: benzene, naphthalene, thlophene, benzothiophene, pyridine, quinoline, indole, furan, benzofuran, thiazole, benzothiazole, imidazole, and benzo-imidazole, the said Ar₁group being possibly substituted with a maximum of 2 residues chosen from among C_1-3alkyl or halo-alkyl, C_1-3alkoxyl or amino-alkoxyl, halogen, OH, NH₂, NR₁₃R₁₄, where R₁₃and R₁₄, which may be the same or different from one another, represent hydrogen or C_1-3alkyl;

R₄represents a group chosen from among:

hydrogen or C_1-6alkyl

L-Q, where L is a chemical bond or a linear or branched C_1-6alkyl residue and Q is a group chosen from among:

i) H, OH, OR₉, NH₂, NR₉R₁₀, guanidine, sulphate, phosphonate, phosphate, where R₉and R₁₀, which may be the same or different from one another, represent a hydrogen, C_1-3alkyl group, C_1-3hydroxyalkyl, C_1-3dihydroxyalkyl, C_1-3alkyl-CONHR₁₂, C_1-3alkyltetrazole, C_1-3alkyl-COOH or wherein R₉R₁₀joined together form with the N-atom a saturated 4-6 membered heterocycle possibly containing a further heteroatom chosen in the group consisting of N, O, S and wherein R₁₂is a mono-, di-, tri-glycosidic group possibly protected with one or more C_1-3-acyl groups or substituted with amino-groups or C_1-3acylamino-groups;

ii) COOH, tetrazole, SO₂NH₂, SO₂NHCOOR₈, CONHR₈, NHCOR₈, where R₈represents a linear or cyclic C_1-6alkyl chain containing one or more polar groups chosen from among the group: OH, NH₂, NR₁₅R₁₆, COOH, CONHR₁₂, PO₃H, SO₃H, OR₁₁and where R₁₅and R₁₆, which may be the same or different from one another, represent a hydrogen or C_1-3alkyl group, and where R₁₁is a C_1-3alkyl or C_2-4amino-alkyl chain, R₁₂is a mono-, di-, tri-glycosidic group possibly protected with one or more C_1-3acyl groups or substituted with amino-groups or C_1-3acylamino-groups or R₁₅R₁₆joined together form with the N-atom a saturated 4-6 membered heterocycle possibly substituted with C_1-3alkyl-groups or with saturated 4-6 membered heterocycle-groups containing at least an N-atom;

iii) COOR₁₇, CONHR₁₂, OR₁₂where R₁₂is a mono-, di- or tri-glycoside group possibly protected with one or more C_1-3acyl groups or substituted with amine or C_1-3acylamine groups and R₁₇is a group R₁₂as above definined or a group C_1-3alkyl, C_1-3alkylphenyl, wherein the phenyl-group can be substituted with a group OH, NO₂, NH₂, CN, CH₃, Cl, Br;

R₅, R₆, R₇, which may be the same or different from one another, represent a hydrogen or C_1-3alkyl group; with the proviso that when R₁and R₂are benzyl or 4-hydroxybenzyl then R₃and R₄are not isopropyl.

Also included in the present invention are the pharmaceutically acceptable salts, the processes for their preparation, and the pharmaceutical compositions containing them.

In view of the presence of chiral centres in the compounds of formula (I), also the individual enantiomers and their mixtures, both in the racemic form and in the non-racemic form, form part of the present invention.

DESCRIPTION OF THE RELATED ART

The NK-2 receptor of tachykinins is widely expressed in the peripheral nervous system of mammals. One of the various effects produced by the selective stimulation of the NK-2 receptor is the contraction of smooth muscle. Hence antagonists of the NK-2 receptor may be considered agents capable of controlling excessive contraction of smooth muscle in any pathological condition in which the release of tachykinins concurs in the genesis of the corresponding disorder.

In particular, the bronchospastic and inflammatory component of asthma, coughing, pulmonary irritation, intestinal spasms, spasms of the biliary tract, local spasms of the bladder and of the ureter during cystitis, kidney infections and colics may be considered conditions in which the administration of NK-2 antagonists may be effective (E. M. Kudlacz et al., Eur. J. Pharmacol., 1993, 241, 17-25).

In addition, a number of NK-2 antagonists capable of surmounting the haemato-encephalic barrier have shown anxiolytic properties (D. M. Walsh et al., Psychopharmacology, 1995, 121, 186-191).

Cyclic compounds, and in particular cyclic hexapeptides (A. T. McKnight et al., Br. J. Pharmacol., 1991, 104, 355) and bicyclic hexapeptides (V. Pavone et al., WO 93/212227) or cyclic hexapseudopeptides (L. Quartara et al., J. Med. Chem., 1994, 37, 3630; S. L. Harbeson et al., Peptides, Chemistry and Biology, Proceedings of the Twelfth American Peptide Symposium, 1992, 124) are known in the literature for their antagonistic activity towards the NK-2 receptor of tachykinins. In EP-A-333174 linear di- and tri-peptide compounds comprising the -D-Trp-Phe-moiety are described; such compounds possess tachykinin antagonism.

It has now surprisingly been found that products of lower molecular weight, monocyclic ones, containing only four bifunctional residues linked together via peptide or pseudopeptide bond, present high pharmacological activity associated to a considerable selectivity for the human NK-2 receptor, and thus are proposed as valid alternatives.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 is a reaction scheme for the general synthesis of compounds of formula (1).

DETAILED DESCRIPTION OF THE INVENTION

The present invention therefore sets itself the aim of making available new monocyclic compounds containing four bifunctional residues linked together via peptide or pseudopeptide bonds having antagonistic action on the NK-2 receptor, with the general formula (I), as defined previously.

Also forming part of the present invention are the pharmaceutically acceptable salts, the processes for their preparation, and the pharmaceutical compositions containing them.

According to the invention preferred compounds of general formula (I) are those in which:

f, g, h, m, which may be the same or different from one another, may be 0 or 1; R₁and R₂, which may be the same or different from one another, represent the side chain of a natural amino acid chosen from among tryptophan, phenyl alanine, tyrosine, histidine or the side chain of a non-natural amino acid chosen in the group:

tryptophan and phenyl alanine, either mono- or di-substituted with residues chosen from among C_1-3alkyl or halo-alkyl, C_1-3alkoxyl or amino-alkoxyl, halogen, OH, NH₂, NR₁₃R₁₄, where R₁₃and R₁₄, which may be the same or different from one another, represent a hydrogen or C_1-3alkyl group;

R₃represents a group chosen from among:

linear or branched alkyl having the formula C_nH_2n+1, with n=1-5 (chosen in the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl) cycloalkyl or alkylcycloalkyl of formula C_nH_2n−1with n=5-9 (chosen in the group consisting of cyclopentyl, cyclohexyl, methylcyclohexyl)

(CH₂)_r—Ar₁, where r=1 or 2 and where Ar₁is an aromatic group chosen from among: α-naphthyl, β-naphthyl, phenyl, indole, the said Ar₁group being possibly substituted with a maximum of 2 residues chosen from among C_1-3alkyl, CF₃, C_1-3alkoxyl, Cl, F, OH, NH₂;

R₄represents an L-Q group where:

L is a chemical bond or CH₂, and

Q is a group chosen from among:

OH, NH₂, NR₉R₁₀, OR₁₁, and where R₉and R₁₀, which may be the same or different from one another, represent a hydrogen or C_1-3alkyl group, C_1-3hydroxy alkyl, C_1-3dihydroxyalkyl, C_1-3alkyl-CONHR₁₂wherein R₁₂is a monoglycosidic group derived from D or L pentoses or hexoses (chosen in the group consisting of ribose, arabinose, glucose, galactose, fructose, glucosamine, galactosamine and their N-acetylated derivatives), C_1-3alkyltetrazole, C_1-3alkyl-COOH or wherein R₉R₁₀are joined together to form with the N atom a morpholine or a piperidine ring and where R₁₁is a C_1-3alkyl chain, or a C_2-4amino-alkyl chain;

NHCOR₈wherein R₈is a cyclohexane containing from 2 to 4 OH groups, a C_1-8alkylchain containing a polar group (chosen in the group consisting of NH₂, COOH, CONHR₁₂(wherein R₁₂is as hereabove defined) or [1,4′]bipiperidine)

COOH, COOR₁₇or CONHR₁₂, wherein R₁₂is as hereabove defined and R₁₇is as R₁₂or a group 4-nitrobenzyl and R₁₂is a monoglycosidic group derived from D or L pentoses or hexoses (chosen in the group consisting of ribose, arabinose, glucose, galactose, fructose, glucosamine, galactosamine and their N-acetylated derivatives).

R₅, R₆, R₇are H.

Likewise preferred are isomers that present an R configuration on the carbon atom that carries the R₃and R₇substituents.

Pharmaceutically acceptable salts of compounds of formula (I) include the salts with inorganic acids (such as, hydrochloric acid, hydrobromic acid, hydrogen iodide, sulphuric acid, nitric acid, phosphoric acid) and organic acids (such as, acetic, propionic, succinic, malonic, citric, tartaric, metasulphonic, para-toluenesulphonic acids), as well as salts of pharmaceutically acceptable bases, both inorganic (such as, hydroxides of sodium, potassium, calcium, magnesium, zinc and aluminium) and organic bases (such as, amines like methyl amine, diethyl amine, triethyl amine, ethyl amine, tromethamine or piperidine).

According to the invention, the compounds of formula (I) containing peptide or pseudopeptide bonds may be obtained by means of classical condensation methods using techniques known in the literature. The general method chosen by us for preparing the peptide compounds (X₁-X₄=—CONR—, —NRCO—) involves the synthesis in solution of the linear peptide chain using amino acids, dicarboxyl; or diamine derivatives suitably protected and, after selective deprotection of the C- and N-terminals, cyclization in polar organic solvents in diluted solution. As method of activation of the carboxyl groups, that using PyBOP and DIEA in DMF or HBT and EDC in DMF are generally preferred.

To provide an example, FIG. 1 presents the general synthesis of compounds of formula (I) in which X₁═X₂═X₃═X₄=—CONH—.

The dicarboxyl precursors 7 containing the R₄group, and the diamine precursors 4 containing the R₃and R₇groups were prepared using methods described in the literature.

In particular, the synthesis of the succinic derivatives, with R₄=alkyl or (CH₂)_n—Ar, is described by R. Conrow et al., J. Org. Chem., 1986, 51, 938 and by S. G. Cohen et al., J. Am. Chem. Soc., 1968, 90, 3495, whilst in the case of R₄=H, amine group, hydroxyl group or carboxyl group, the following were respectively used: succinic anhydride, aspartic acid, malic acid or carboxysuccinic acid appropriately protected.

The synthesis of the ethylene diamine derivatives containing the R₃, R₇groups was performed starting from the corresponding N-protected amino acids by reduction of the carboxyl to alcohol with BH₃.THF (C. F. Stanfield et al., J. Org. Chem., 1981, 46, 4797, 4799; I. R. Ollmann et al., Bioorg. Med. Chem., 1995, 3, 969), conversion to azide via the corrisponding mesylate and subsequent reduction to amino group (P. G. Mattingly, Synthesis, 1990, 366; P. M. O'Brien et al., J. Med. Chem., 1994, 37, 1810).

The compounds containing reduced peptide bonds (X₁-X₄=—CH₂—NR—, —NR—CH₂—) were synthesized in solution according to known methods, such as reductive amination of the aldehyde of an amino acid with the amine function of a protected amino acid or peptide, in the presence of NaCNBH₄as reducer in DMF/AcOH (K. A. Jacobson et al., J. Med. Chem., 1983, 26, 492; R. F. Borch et al. J. Am. Chem. Soc., 1971, 93, 2897; J. P. Salvi et al., Tetr. Lett., 1994, 35, 1181). The aldehydes were obtained by reduction with LiAlH₄of the corresponding protected amino acids, N,O-dimethylhydmxy-amates according to the method described by J. A. Feherentz et al., Synthesis, 1983, 676 and Int. J. Peptide Res., 1985, 26, 236.

The compounds of formula 10 wherein R₄is NH₂or COOH can be derivatized into compounds of formula 1 wherein R₄is NR₉R₁₀, guanidine, tetrazole, NHCOR₈, CONHR₈, COOR₁₇, CONHR₁₂, wherein R₉, R₁₀, R₈, R₁₂and R₁₇are as above defined, according to known methods.

The compounds of formula (I) as specified above have proved to be powerful antagonists of the NK-2 receptor of tachykinins, and hence can be administered as agents capable of controlling any central or peripheral manifestation due to excessive activation of tachykinergic neurons, and in particular excessive contraction of smooth muscle in any pathological condition in which release of tachykinins concurs in the genesis of the corresponding disorders.

In particular, the bronchospastic and inflammatory component of asthma, of coughing, of pulmonary irritation, intestinal spasms, spasms of the biliary tract, and local spasms of the bladder and ureter in the course of cystitis and kidney infections and colics may be considered conditions in which the administration of the compounds of formula (I), as NK-2 antagonists, may prove effective.

The use as anxiolytic agents should also be considered for those compounds that are provided with the appropriate chemico-physical characteristics for penetration into the CNS.

The compounds of formula (I) that are the subject of the present invention are suited for administration for therapeutic purposes to higher animals and man through the parenteral, oral, inhalational and sublingual routes, achieving pharmacological effects according to the properties described above. For administration through parenteral (intravenous, intramuscular, and intradermal) routes, sterile or lyophilized preparations are used. As far as the nasal, inhalational and sublingual instillation routes are concerned, aqueous solutions, aerosol preparations, powders or capsules are used according to the particular case.

The doses of active principle in the aforesaid compositions may range between 0.02 and 10 mg/kg of body weight.

The invention will now be illustrated in the examples that follow, which, however, have no limiting effect.

EXAMPLE 1 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH—]}

(compound of formula (I) where: X₁═X₂═X₃═X₄=—CO—NH—; R₁=—CH₂-(indol-3-yl); R₂═R₃=—CH₂—C₆H₅; R₄═R₅═R₆═R₇═H; m=h=0, f=g=1; the carbon atoms C—R₁and C—R₂have an S configuration, whereas C—R₃has an R configuration)

a) Synthesis of BOC-Trp-Phe-OH Dipeptide

Di-tert-butyl carbonate (3.4 g) was added to a solution of H-Trp-Phe-OH (5 g) in dioxane (30 ml), H₂O (15 ml) and NaOH 1M (15.6 ml), cooled to 0-5° C. under stirring. The reaction mixture was kept stirred for 2 hours, and then concentrated and extracted with pentane (2×20 ml). The aqueous phase was cooled with ice, with the addition of AcOEt (50 ml), KHSO₄to obtain pH 2-3, separated and extracted with AcOEt (2×50 ml). The re-united organic phases were washed with brine (50 ml), vacuum dried and evaporated at 30° C. to obtain 6 g of the desired compound as a white semi-solid residue.

TLC: r.f. 0.55 (chloroform/cyclohexane/ACOH/H₂O=45/45/5/5), 0.52. (CHCl₃/MeOH=9/1).

b) Synthesis of (R)-1-benzyl-2-benzyloxycarbonylamino-ethyl amine

The synthesis was carried out following the method described by P. G. Mattingly, Synthesis, 1990, 366, starting from BOC-D-phenylalaninol

c) Synthesis of BOC-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH-Z] (5)

(R)-1-benzyl-2-benzyloxycarbonylamino ethyl amine (750 mg), PyBOP (1.37 g), and DIEA (0.9 ml) were added to a solution of BOC-Trp-Phe-OH (1.19 g, 2.63 mmol.) in anhydrous DMG (10 ml) under nitrogen.

The reaction mixture was kept stirred overnight at room temperature, AcOEt (80 ml) was added, and the mixture was washed with HCl 1N (3×30 ml), Na₂CO₃5% (3×30 ml), and H₂O (30 ml). The organic phase was vacuum evaporated at 30° C. to obtain 1.8 g of an ivory-coloured solid residue.

The crude compound was purified by washing in suspension with AcOEt under heat and with MeOH at room temperature to obtain 1.15 g of the desired product 5 as a white solid. MS(TS): [MH⁺]=718

d) Synthesis of H-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH-Z] (6)

TFA (6 ml) was added, under stirring and at room temperature, to a suspension of the compound 5 (1.1 g) in CHCl₃(30 ml), and a clear solution was seen to form immediately. The reaction mixture was kept stirred for 1.5 hours, and the disappearance of the precursor was monitored by means of HPLC analysis. After evaporation of the solvent, the residue was diluted with AcOEt (100 ml), washed with NaHCO₃5% (2×30 ml) and brine (30 ml).

The organic phase was dried with MgSO₄and vacuum evaporated at 30° C. The solid residue was purified by means of flash-chromatography (CHCl₃/MeOH=95/5) to obtain 821 mg of the desired compound 6 as a white solid.

TLC: r.f. 0.50 (CHCl₃/MeOH=9/1).

e) Synthesis of HO-Suc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH-Z] (Compound 8 where: PG₂=OH; PG₁=Z)

NEt₃(0.095 ml) and succinic anhydride (68 mg) were added to a solution of compound 6 (420 mg) in anhydrous DMF (10 ml) under stirring and at room temperature. The reaction mixture was kept stirred at room temperature for 4 hours.

After evaporation of the solvent, the residue was suspended in H₂O and kept stirred for 5 minutes. The solid was filtered and washed in suspension twice using MeOH to obtain 242 mg of the desired compound 8 as a white solid.

TLC: r.f. 0.50 (CHCl₃/MeOH=8/2).

f) Synthesis of HO-Suc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH₂] (9)

The compound 8 (225 mg) was suspended in MeOH (10 ml) and hydrogenated in the presence of Pd/C 10% (50 mg) at atmospheric pressure and room temperature. HPLC analysis after 4 hours showed that the precursor had disappeared completely.

The catalyst was filtered and washed with MeOH. After evaporation of the solvent, 158 mg of the desired compound 9 were obtained as a white solid.

m.p.=142-4° C.; TLC: r.f. 0.70 (n-butanol/AcOH/H₂O=6/2/2)

g) Synthesis of cyclo{Suc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH—]}-(10) PyBOP (145 mg) and DIEA (0.09 ml) were added to a solution of compound 9 (148 mg) in anhydrous DMF (5 ml) stirred under nitrogen.

The reaction mixture was kept stirred for 5 hours and, after evaporation of the solvent, the residue was suspended in AcOEt, kept stirred for 10 minutes, and filtered, to obtain 100 mg of a solid product.

Part of the product (50 mg) was purified by HPLC to obtain 18 mg of the desired compound 10 as a white solid.

MS (TS): [MH⁺]=566; 1H-NMR (DMSO): d 2.15-2.35 (m, 2H), 2.55-2.85 (m, 8H), 2.96-3.04 (m, 2H), 3.90-4.02 (m, 1H), 4.03-4.15 (m, 1H), 4.25-4.42 (m, 1H), 6.71 (d, 1H), 6.90-7.42 (m, 16H), 8.09 (m, 1H), 8.50 (d, 1H), 10.82 (s, 1H).

Following the procedure described in Example 1, the compounds specified below were obtained:

EXAMPLE 2 Cyclo{-Suc-Trp-Phe-[(S)—NH—CH(CH₂C₆H₅)—CH₂—NH—]}

(compound of formula I in which the substituents are defined as in Example 1, but all the C—R₁, C—R₂and C—R₃atoms have an S configuration) 1H-NMR (DMSO): d 1.95-2.32 (m, 2H), 2.34-2.90 (m, 6H), 2.92-3.18 (m, 2H), 3.60-3.82 (m, 1H), 4.00-4.40 (m, 4H), 6.90-7.36 (m, 14H), 7.39-7.54 (m, 2H), 7.64 (d, 1H), 7.88 (t, 1H), 8.27 (d, 1H), 10.78 (s, 1H).

EXAMPLE 3 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₁₁)—CH₂—NH—]}

(compound of formula I in which X₁═X₂═X₃═X₄=CO—NH—; R₁=CH₂-(indol-3-yl); R₂=—CH₂—C₆H₅; R₃=—CH₂—C₆H₁₁; R₄═R₅═R₇═H; m=h=0, f=g=1; the carbon atoms C—R₁and C—R₂have an S configuration, whereas C—R₃has an R configuration) 1H-NMR (DMSO): d 0.65-0.95 (m 2H), 1.00-1.38 (m, 6H), 1.45-1.75 (m, 5H), 2.05-2.30 (m, 2H), 2.40-2.85 (m, 6H), 3.20-3.60 (m, 1H), 3.61-3.78 (m, 1H), 3.80-3.96 (m, 1H), 3.98-4.10 (m, 1H), 4.38-4.55 (m, 1H), 8.47 (d, 1H), 6.90-7.45 (m, 11H), 8.02 (m, 1H), 8.47 (d, 1H), 10.78 (d, 1H).

EXAMPLE 4 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₄(4-OCH₃))—CH₂—NH—]}

(compound of formula I in which X₁═X₂═X₃═X₄=CO—NH—; R₁=—CH₂-(indol-3-yl); R₂=—CH₂—C₆H₅; R₃=—CH₂—C₆H₄(4-OCH₃): R₄═R₅═R₆═R₇═H; m=h=0, f=g=1; the carbon atoms C—R₁and C—R₂have an S configuration, whereas C—R₃has an R configuration) 1H-NMR (DMSO): d 2.13-2.37 (m, 2H), 2.50-2.85 (m, 8H), 3.25-3.50 (m, 1H), 3.58-3.80 (m, 4H), 3.85-4.00 (m, 1H), 4.02-4.18 (m, 1H), 4.28-4.45 (m, 1H), 6.65-7.47 (m, 16H), 8-02-8.16 (m, 1H), 8.48 (d, 1H), 10.80 (s, 1H).

EXAMPLE 5 Cyclo{-Suc-Trp(5F)-Phe[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH—]}

(compound of formula I, in which R₁=—CH₂-(5-fluoroindol-3-yl), and the other substituents are as defined in Example 1) MS(ES+): [MH+]=584

EXAMPLE 6 Cyclo{-Suc-Trp(Me)-Phe[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH—]}

(compound of formula I, in which R₁—CH₂-(N-methylindol-3-yl), and the other substituents are as defined in Example 1) MS(ES+):[MH+}=580

EXAMPLE 7 Cyclo{-Suc-Phe(3,4-Cl)-Phe-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH—]}

(compound of formula I, in which R₁=-(3,4-dichlarobenzyl), and the other substituents are as defined in Example 1) MS(ES+):[MH+}=595

EXAMPLE 8 Cyclo{-Suc-Trp-Phe(3,4-Cl)-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH—]}

(compound of formula I, in which R₂=-(3,4-dichlarobenzyl), and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=634

EXAMPLE 9 Cyclo{-Suc-Trp-Tyr-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH-—]}

(compound of formula I, in which R₂=-(4-hydroxybenzyl), and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=582

EXAMPLE 10 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₃-3,4-diCl)-CH₂—NH—]}

(compound of formula I, in which R₃=-(3,4-dichlorobenzyl), and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=634

EXAMPLE 11 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₄-4-OH)—CH₂—NH—]}

(compound of formula I, in which R₃=-(4-hydroxybenzyl), and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=582

EXAMPLE 12 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂—CH₂—C₆H₅)—CH₂—NH—]}

(compound of formula I, in which R₃=—CH₂—CH₂—C₆H₅, and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=580

EXAMPLE 13 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂-2-naphthyl)-CH₂—NH—]}

(compound of formula I, in which R₃=—CH₂-(2-naphthyl), and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=616

EXAMPLE 14 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂-indol-3-yl)-CH₂—NH—]}

(compound of formula I, in which R₃=—CH₂-(indol-3-yl), and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=605

EXAMPLE 15 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂-5-F-indol-3-yl)—CH₂—NH—]}

(compound of formula I, in which R₃=—CH₂-(5-fluoroindol-3-yl), and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=623

EXAMPLE 16 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₄-3-F)—CH₂—NH—]}

(compound of formula I, in which R₃=—CH₂C₆H₄-3-F, and the other substituents are as defined in Example 1) (MS(ES+):[MH+}=584

EXAMPLE 17 Cyclo{-Suc-Trp-Phe-[(R)NH—CH(CH₂—C₆H₃-3,4-diF-CH₂—NH]—}

(compound of formula (I) wherein R₃=-(3,4-difluorobenzyl) and the other substituents are as defined in Example 1 MS (ES+): [MH+]=602

EXAMPLE 18 Cyclo{-Suc-Trp-Phe-[(R)NH—CH(CH₂—C₆H₄-4-CF₃—CH₂—NH]—}

(compound of formula (I) wherein R₃=-(4-trifluoromethylbenzyl) and the other substituents are as defined in Example 1) MS (ES+): [MH+]=634

EXAMPLE 19 Cyclo{-Suc-Trp-Phe-[(R)—NH—CH₂—CH(CH₂C₆H₅)—NH—]}

(compound of formula (I) where: X₁═X₂═X₃═X₄=—CO—NH—; R₁=—CH₂-(indol-3-yl); R₂═R₃=—CH₂—C₆H₅; R₄═R₅═R₆═R₇=H; f=h=0; m=g=1; the carbon atoms C—R₁and C—R₂have an S configuration, whereas C—R₃has an R configuration)

a) Synthesis of (R)-2-tert-butoxycarbonylamino-3-phenyl-propylamine

The synthesis was performed according to the method described by P. G. Mattingly, Synthesis, 1990, 366, starting from BOC-D-phenylalaninol.

b) Synthesis of Z-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—NH-BOC] (5)

(R)-2-tert-butoxycarbonylamino-3-phenyl-propylamine (titre 65%, 1.1 g), PyBOP (1.45 g), and DIEA (0.98 ml) were added to a solution of Z-Trp-Phe-OH (1.4 g) in anhydrous DMF (15 ml) under nitrogen. The reaction mixture was kept stirred overnight at room temperature, AcOEt (100 ml) was added, and the mixture was washed with HCl 1N (3×30 ml), Na₂CO₃5% (3×30 ml), and H₂O (30 ml). During the washings, the product partly precipitated, and was filtered and re-united to the organic phase. After vacuum evaporation of the solvent, the residue (2.4 g) was washed in suspension with AcOEt and vacuum dried on P₂O₅, to obtain 1.79 g of the desired compound 5 as a white solid.

TLC: r.f. 0.86 (CHCl₃/MeOH=95/5); r.f. 0.78 (AcOEt).

c) Synthesis of H-Trp-Phe-[(R)—NH—CH₂—CH(CH₂—C₆H₅)—NH-BOC] (6)

A suspension of the compound 5 (1.7 g) in MeOH (350 ml) was hydrogenated in the presence of Pd/C 10%, at atmospheric pressure and room temperature, until the precursor disappeared (HPLC analysis). After elimination of the catalyst by filtration and vacuum evaporation of the solvent, the residue was washed in suspension with AcOEt to obtain 890 mg of the desired compound 6 as a white solid.

TLC: r.f. 0.38 (CHCl₃/MeOH=9/1), r.f. 0.26 (AcOEt).

d) Synthesis of HO-Suc-Trp-Phe-[(R)—NH—CH₂—CH(CH₂—C₆H₅)—NH-BOC] (compound 8 where: PG₂=OH; PG₁=BOC)

Succinic anhydride (158 mg) and NEt₃(0.21 ml) were added to a solution of compound 6 (840 mg) in anhydrous DMF (20 ml) under nitrogen. The reaction mixture was kept stirred at room temperature overnight. After vacuum evaporation of the solvent at a temperature of 30° C., the residue was treated with H₂O at 40-50° C., filtered, washed in suspension with MeOH (15 ml), and vacuum dried to obtain 600 mg of the desired compound 8 as a white solid.

TLC: 0.63 (CHCl₃/MeOH=8/2).

e) Synthesis of HO-Suc-Trp-Phe-[(R)—NH—CH₂—CH(CH₂—C₆H₅)—NH₂.TFA (9 TFA)

TFA (2 ml) was added, under stirring, to a suspension of compound 8 (560 mg) in CH₂Cl₂(15 ml), and a clear solution was obtained. After 2 hours at room temperature, the solvent was evaporated, and the residue diluted with ether, filtered and dried to obtain 500 mg of the desired compound 9 TFA as an ivory-coloured solid.

TLC: 0.58 (CHCl₃/MeOH=8/2), 0.74 (n-butanol/AcOH/H₂O=6/2/2).

f) Synthesis of cyclo{-Suc-Trp-Phe-[(R)—NH—CH₂—CH(CH₂—C₆H₅)—NH—]} (10)

PyBOP (447 mg), and DIEA (0.37 ml) were added, under nitrogen, to a solution of 9 TFA (500 mg) in anhydrous DMF (20 ml). The reaction mixture was kept stirred overnight at room temperature, After evaporation of the solvent, the residue was washed in suspension with citric acid 5% and H₂O. The product was dried on P₂O₅, washed in suspension using AcOEt and MeOH under heat, to obtain 110 mg of a solid. A portion was purified by HPLC to obtain 25 mg of the desired compound 10 as a white solid.

1H-NMR (DMSO): d 2.10-2.40 (m, 4H), 2.45-2.58 (m, 1H), 2.60-3.05. (m, 7H), 3.80-3.90 (m, 1H), 3.92-4.05 (m, 1H), 4.20-4.38 (m, 1H), 6.90-7.40 (m, 16H), 7.52-7.58 (m, 1H), 8.11 (d, 1H), 8.37 (d, 1H), 10.79 (s, 1H).

EXAMPLE 20 Cyclo{-Suc-Trp-Phe-[(S)—NH—CH₂—CH(CH₂C₆H₅)—NH—]}

(compound of formula I in which the substituents are defined as in Example 19, except for the fact that C—R₃has an S configuration).

The compound was obtained following a procedure similar to that described for

EXAMPLE 19

1H-NMR (DMSO): d 1.98-2.26 (m, 2H), 2.40-2.88 (m, 8H), 2.98-3.11 (m, 1H), 3.66-3.84 (m, 1H), 3.98-4.23 (m, 2H), 4.40-4.58 (m, 1H), 6.89-7.48 (m, 17H), 8.10 (d 1H), 8.44 (d, 1H), 10.83 (s. 1H).

Proceeding in a similar way as that described in Example 1 above, the following compounds were obtained:

EXAMPLE 21 Cyclo{-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH—]—(CH₂)₃CO—}

(compound of formula I, in which R₃=—CH₂—C₆H₅and X₃=—CH₂—NH—, and the other substituents are as defined in Example 1. MS (ES+): [MH+)=552.

EXAMPLE 22 Cyclo{-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—N(CH₃)]—(CH₂)₃CO—}

(compound of formula I, wherein R₃=—CH₂—C₆H₅and X₃=—CH₂N(CH₃)— and the other substituents are as defined in Example 1. MS(ES+):[MH+]=566.

EXAMPLE 23 Cyclo{-Suc[1(S)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(compound of formula I wherein h=1, g=0, R₄=—NH₂and the other substituents are as defined in Example 1 while the carbon atom C—R₄has configuration S).

a) Synthesis of Boc-Asp[Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂—NH-Z]-OBz](compound 8 wherein: PG₂=OBzl, PG₁=Z

To a solution of compound 6 (see Example. 1d) (650 mg) in anhydrous DMF (30 ml) Boc-Asp-OBzl (340 mg), PyBOP (656 mg) and ET₃N (0.4 ml) are added under stitrring at room temperature. The mixture is stirred for 2 h at room temperature. After evaporation of the solvent under vacuum the residue was treated with H₂O giving a solid residue which is filtered, washed with water and dryed. The solid was recrystallized from ethanole giving 640 mg of the desired compound 8 in the form of a white solid.

MS (ES+): [MH+}=923; HPLC performed in the following conditions: silica column C₁₈particles size 5 μm and pores of 100 A (analitical data: 20% carboon and C₁₈Surface Coverage 3.3 μmoles/m²), lenght: 3.9×150 mm; mobile phase having a linear gradient of acetonitrile containing 0.1%(v/v) TFA (phase B) against aqueous TFA 0.1% (v/v) (phase A), from 20% to 80% in B in 20 minutes at a flux of 3 ml/min; determination by UV at 220 nm. Retentio time: Rt=21.1 min.

b) Synthesis of Boc-Asp[Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂—NH₂]}—OH (9)

The compound 8 (of Example 23a) (600 mg) was solved in DMF (2 ml) and diluted with MeOH (30 ml), hydrogenated in the presence of Pd/C 10% (100 mg) at room pressure and temperature for 5 h. The catalyser was filtered and washed with MeOH. After evaporation of the solvent 420 mg of the desired product 9 were obtained in the form of a white solid.

MS(ES+):[MH+]=663; HPLC (same conditions as above): Rt=11.07.

c) Synthesis of cyclo{-Suc[1(S)NH-BOC]-Trp-Phe[(R)NH—CH(CH₂—CH₆H₅)—CH₂—NH]—} (10)

To a solution of compound 9 (see, example 23b) (7.2 g) in anhydrous DMF (900 ml) 4 g of HBT and 2 g of EDC were added under stirring and nitrogen atmosphere. The mixture was stirred for 5 h and, after evaporation of the solvent, the residue was treated with an aqueous solution of KHSO₄5% and extracted in ethylacetate.

The organic phase was washed with brine, NaHCO₃5% and again with brine, dried and evaporated the yellow solid obtained (5.2 g) was crystallized from isopropanole/water 1/1 giving 3.2 g of a white solid. MS(ES+):[MH+]=681;

HPLC (same conditions as above): Rt=14.8.

d) Synthesis of cyclo{-Suc[(1(S)NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂—NH]} (10)

To a suspension of compound 10 (see example 23d) (1 g) in CH₂Cl₂(20 ml) TFA (7 ml) was added under stirring at 0° C. giving a clear solution; thereafter the temerature is raised up to room temperature. The mixture was left at room temperature for 90 minutes and then the solvent was evaporated and the residue was treated with NaHCO₃and water and extracted in ethylacetate. The organic phase was washed with brine, dried and evaporated giving a solid (800 mg).

MS(ES+).[MH+}=581; HPLC (same conditions as above said): Rt=9.4.

A sample of 20 mg is purified by HPLC giving 15 mg of trifluoroacetate: cyclo{-Suc[1(S)NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H_5)—CH ₂—NH]—}.TFA (10 TFA) MS(ES+):[MH+]=581; HPLC: Rt=9.4 (same conditions as above); 1H-NMR (DMSO): δ 2.60-2.90 (m, 8H), 3.05-3.11 (m, 1H), 3.63-3.71 (m, 1H), 4.07-4.13 (m, 3H), 4.32-4.38 (m, 1H), 6.90-7.45 (m, 17H), 8.07 (bs, NH₃ ⁺), 8.22-8.28 (m, 1H), 8.57 (d, 1H), 10.82 (s, 1H).

Following the procedure described in Example 23 the following compounds were obtained:

EXAMPLE 24 Cyclo{-Suc[1(R)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(compound of formula I wherein h=1, g=0, R₄=—NH₂and the other substituents are as defined in Example 1 while the carbon atom C—R₄ha configuration R) MS (ES+): [MH+]=581

EXAMPLE 25 Cyclo{-Suc[2(S)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(compound of formula I wherein h=1, g=0, R₄=—NH₂and the other substituents are as defined in Example 1 while the carbon atom C—R₄ha configuration S) MS (ES+): [MH+]=581

EXAMPLE 26 Cyclo{-Suc[2(R)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]}

EXAMPLE 27 Cyclo{-Suc[1(S)—NH(CH₃)]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(compound of formula I wherein h=1, g=0, R₄=—NH(CH₃) and the other substituents are as defined in Example 1 while the carbon atom C—R₄ha configuration S) MS (ES+): [MH+]=595

EXAMPLE 28 Cyclo{-Suc[1-COO(CH₂—C₆H₄-4-NO₂)]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(compound of formula I wherein h=1, g=0, R₄=—COO(CH₂—CH₆H₄-4-NO₂) and the other substituents are as defined in example 23) (diasteroisomeric mixture in respect of C—R₄and separation of the two epimers).

a) Synthesis of Boc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH₂]

The Boc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH-Z] (5 see example 1c) (1.2 g) was dissolved in a mixture of DMF (30 ml) and MeOH (200 ml) and hydrogenized in the presence of Pd/C 10% (200 mg) at room pressure and temperature, for 4 h. The catalyser was filtered and washed with MeOH, the solvent evaporated giving 700 mg of solid residue.

MS(ES+): [MH+] 584; HPLC (conditions of example 23): Rt=11.1.

b) Boc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—COCH[COO(CH₂—C₆H₄-4-NO₂)]CH₂COO-tBu

424 mg of 2-(4-nitro-benzyloxycarbonyl)-succinic acid 4-tert-butyl ester were dissolved in DMF (20 ml). To the mixture HOBT (490 mg), EDC and Boc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH₂] were added at 0° C. under stirring; the temperature was raised to room temperature while stirring for 2 h. The solvent was evaporated and the residue treated with KHSO₄5% giving a yellow solid which was filtered, washed with NaHCO₃5%, water and dried.

1.05 g of compound were obtained, MS(ES+):[MH+]=919; HPLC (conditions of Example 23): Rt=20.36

c)H-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—COCH[COO(CH₂—C₆H₄-4-NO₂)]CH₂COOH

Boc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—COCH[COO(CH₂—C₆H₄-4-NO₂)]CH₂COO-tBu (1.05 g) was added in small portions in anhydrous trifluoroacetic acid (20 ml) at 0° C. and the mixture was kept under stirring for 30 minutes, dried and the residue treated with ethyleter; the formed solid was filtered, washed with ethyleter and dried, 850 mg of product were obtained.

MS(ES+):[MH+]=763: HPLC (conditions of example 23): Rt=10.6.

d) Synthesis of cyclo{-Suc[1-COO(CH₂C₆H₄-4-NO₂)]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH—]}

The H-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—COCH[COO(CH₂C₆H₄-4-NO₂)]CH₂COOH (100 mg) was dissolved in DMF (5 ml) and to the mixture PyBOP (80 mg) and Et₃N (54 μl) were added stirring for 3 h.

The reaction mixture was dried and the residue dissolved in ethylacetate, the organic phase was washed with KHSO₄5%, brine, NaHCO₃5% and brine, dried and concentrated. 90 mg of epimeric mixture was obtained, the epimers were separated by HPLC giving:

30 mg of liophylized solid which in HPLC (conditions of example 23) shows an Rt=15.2. MS(ES+):[MH+]=745.

1H-NMR (DMSO): δ 2.54-2.81 (m, 7H), 3.08-3.17 (m, 1H), 3.34-3.39 (m, 1H), 3.77-3.84 (m, 1H), 4.00-4.10 (m, 3H), 4.37-4.43 (m, 1H), 5.31 (s, 2H), 6.60 (d, 1H9, 6.93-7.42 (m, 16H), 7.62 (d, 2H), 8.24 (d, 2H), 8.60 (d, 1H), 8.66-8.72 (m, 1H), 10.81 (s, 1H) and

7 mg of liophylized solid which in HPLC (conditions of example 23) shows an Rt=15.7. MS(ES+): [MH+]=745.

EXAMPLE 29

Cyclo{-Suc(1-COOH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH_]} (compound of formula I, wherein h=1, g=0, R₄=—COOH and the other substituents are as defined in Example 1) [epimer which in HPLC (conditions of Example 23) shows an Rt=10.7]

The cyclo{-Suc(1-COO(CH₂—C₆H₄-4-NO₂)]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH_]} which in HPLC (same conditions as in example 23) shows an Rt=15.2 (50 mg) was suspended in a mixture water/isopropanole:1/1 (6 ml) containing K₂CO₃(19 mg) and was kept under stirring for 24 h. The solvent was evaporated and the residue was diluted with water and the solution washed with ethylacetate, by adding HCl 1N separated a solid which was extracetd with ethylacetate; the organic phase was washed with brine and dried. By evaporating the solvent mg 35 of a solid residue were obtained.

MS(ES+):[MH+]=610. HPLC (conditions of Example 23): Rt=10.7.

EXAMPLE 30

Cyclo{-Suc(1-COOH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH_]} (compound of formula I, wherein h=1, g=0, R₄=—COOH and the other substituents ar as defined in Example 1) [epimer which in HPLC (conditions as in Example 23) shows an Rt=11.1]

The cyclo{-Suc(1-COO(CH₂—C₆H₄-4-NO₂)]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂-NH_]} having Rt=15.7 was hydrolized as described in Example 29.

MS(ES+):[MH+]=610; HPLC (same conditions of Example 23): Rt=11.1.

As described in Example 28 the following compounds weer obtained:

EXAMPLE 31 Cyclo}-Suc(1-OH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH—]}

(compound of formula I, in which h=1; g=0; R₄=—OH, and the other substituents are as defined in Example 1), MS(ES+):[MH+]=582.

EXAMPLE 32 Cyclo{-Suc(2-COOH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH—]}

(compound of formula I, in which R₄=—COOH, and the other substituents are as defined in Example 1) MS(ES+):[MH+]: 610.

EXAMPLE 33 Cyclo{-Suc(2OH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH—]} (compound of formula I wherein: h=0, g=1, R₄=OH and the other substituents are as defined in example 1) MS(ES+): [MH+]=582.

The compounds of Examples 23, 24, 25, 26, 27, 29, 30 and 32 can be derivatized as described hereinafter.

EXAMPLE 34

Cyclo{-Suc[1(S)-(2H-tetrazolyl-5-ylmethyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}.TFA (compound of formula I wherein h=1, g=0, R₄=-(2H-tetrazolyl-5-ylmethyl)amino and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

a) Synthesis of, 5-iodomethyl-1-trityl-1H-tetrazole

To a suspension of 5-chloromethyl-1H-tetrazole (6.0 g) in chloroform (100 ml) trityl-chloride (14.2 g) was added at 0° C. under nitrogen, and the mixture was stirred up to total solubilization, thereafter a solution of Et₃N (7.0 ml) in chloroform (50 ml) was added at 5° C. and the temperature was left raising up to room temperature, the mixture was kept resting for 24 h.

The mixture was treated with ethylacetate (200 ml) and left resting for 6 h, the separated solid was filtered away and to the solution acetone (70 ml) was added, the precipitated solid was collected by filtration and dried giving 9.5 g of 5-chloromethyl-1-trityl-1H-tetrazole which was solubilized in acetone (200 ml) at 60° C. Sodium iodide (5.6 g) was added to the solution which was refluxed for 6 h, by cooling precipitated a compound which was filtered, washed with water and dried giving 5.2 g of a white solid.

TLC: R.f. 0.55 (AcOEt/Cyclohexane: 1/3).

b) Synthesis of cyclo{-Suc[1(S)-(2-trityl-tetrazolyl-5-ylmethyl)amino]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

To 205 mg of cyclo{-Suc[1(S)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}(compound of example 23) in anhydrous DMF (5 ml) were added, under stirring 5-iodomethyl-1-trityl-1H-tetrazole (147 mg) and thereafter DIEA (0.06 ml) keeping the temperature at 0° C. for 4 h and at room temperature for 3 h. The mixture was treated with water and extracted with ethylacetate, the organic phase was washed with brine and dried. By evaporating the solvent a solid was obtained which was purified by column-chromatography eluting with AcOEt/MeOH=9515. 210 mg of product were obtained. MS(ES+):[MH+]=905;

HPLC (conditions of example 23): Rt=15.4.

c) synthesis of cyclo{-Suc[1(S(2-Hl-tetrazolyl-5-ylmethyl)amino]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}.TFA

To a solution of cyclo{-Suc[1(S)-(2-trityl-tetrazolyl-5-ylmethyl)amino]Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]-} (90 mg) in anhydrous DMF (5 ml) a solution of HCl 4M in dioxane (0.6 ml) was added at 0°-5° C., the temperature was brought to room temperature and the mixture was left resting up to end of the reaction (14 h at room temperature and 56 h at 5° C.) checking the reaction by HPLC. The solvent was evaporated and the residue treated with AcOEt, the organic phase was washed with brine and dried; evaporating the solvent 30 g of a crude solid are obtained, the solid is purified by HPLC giving 10 g of liophilyzed solid product.

MS(ES+):[MH+]=663; HPLC (conditions of example 23): Rt=9.0.

1H-NMR (DMSO): δ 2.62-2.92 (m, 8H), 3.16-3.23 (m, 1H), 3.68-3.74 (m, 1H), 4.00-4.14 (m, 3H), 4.25-4.75 (m, 3H), 6.88-7.42 (m, 17H), 8.30-8.37 (m, 1H). 8.54 (d, 1H), 10.82 (s, 1H).

EXAMPLE 35

Cyclo{-Suc[1(S)-(morpholin-4-yl)]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}.TFA (compound of formula I wherein h=1, g=0, R₄=-(morpholin-4-yl) and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

To a solution of 2.2′-oxydiacetaldheyde (1 mmole), excess, in methanole (20 ml) 58 mg of cyclo{-Suc[1(S)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—} (compound of example 23), 0.2 ml of acetic acid and 12 mg of NaCNBH₃were added. After 2 h the mixture was diluted with water (10 ml), treated with HCl 1N up to pH 3 and the methanole was evaporated; the solution was treated with NaHCO₃5% and the formed solid was extracted with ethylacetate. The organic phase, after washing with brine and anhydrification, was evaporated giving 58 mg of a solid which was purified by HPLC giving 10 mg of liophylized solid trifluoroacetate.

MS(ES+):[MH+]=651; TLC: R.f.0.20 (CHCl₃/MeOH:9/1).

1H-NMR (DMSO): δ 2.62-3.00 (m, 8H), 3.27-3.87 (m, 10H), 4.07-4.15 (m, 3H), 4.32-4.38 (m, 1H), 6.62 (d, 1H), 6.94-7.41 (m, 16H), 8.49-8.64(m, 2H), 10.84 (s, 1H).

Via a similar reductive amination reaction, as described in example 35, the following compounds were obtained:

EXAMPLE 36

Cyclo{-Suc[1(S)—N(CH₃)₂]-Trp-Phe-[(R)—NH—CH(CH₂—C_6H ₅)—CH₂NH]—}.TFA (compound of formula I wherein h=1, g=0, R₄=—N(CH₃)₂and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The synthesis was performed starting from the compound of example 23 using paraformaldheyde. MS(ES+):[MH+]=609.

EXAMPLE 37

Cyclo{-Suc[1(S)-(piperidin-4-yl)]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂NH]—}.TFA (compound of formula I wherein h=1, g=0, R₄=-(piperidin-4-yl) and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The synthesis was performed starting from the compound of example 23 using glutaraldheyde. MS(ES+):[MH+]=649.

EXAMPLE 38

Cyclo{-Suc[1(S)—(N(CH₂CH₂OH)₂)]-Trp-Phe-[(R)—NH—CH(CH₂—C_6H ₅)—CH₂—NH]—}.TFA (compound of formula I wherein h=1, g=0, R₄=—N(CH₂CH₂OH)₂and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The synthesis was performed starting from the compound of example 23 using HE glycolaldheyde. MS(ES+):[MH+]=669.

EXAMPLE 39

Cyclo{-Suc[1(S)—(NHCH₂CH(OH)CH₂OH]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}.TFA (compound of formula I wherein h=1, g=0, R₄=—NHCH₂CH(OH)CH₂OH and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The synthesis was performed starting from the compound of example 24 using D-glyceraldheyde. MS(ES+):[MH+]=655.

EXAMPLE 40

Cyclo{-Suc[1(S)-(3-carboxypropanoyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}. (compound of formula I wherein h=1, g=0, R₄=-(3-carboxypropanoyl)amino and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

To a solution of the compound of Example 23 (100 mg) in anhydrous DMF (2 ml) succinic anhydryde (30 mg) and dimethylamino-piridine (10 mg) were added and the solution was stirred for 16 h; the solvent was evaporated giving a solid which was solubilized in ethylacetate, washed with citric acid 10%, brine and dried. By evaporating the solvent a solid compound was collected (90 mg), which purified by HPLC gave 60 mg of a liophylized solid.

MS(ES+):[MH+]=681; HPLC (conditions as in example 23): Rt=10.8.

1H-NMR (DMSO): δ 2.35-2.82 (m, 12H), 3.25-3.28 (m, 1H), 3.66-3.73 (m, 1H), 3.98-4.12 (m, 2H), 4.33-4.38 (m, 1H), 4.67-4.73 (m, 1H), 6.80 (d, 1H), 6.96-7.39 (m, 16H), 8.16-8.23 (m, 2H), 8.51 (d, 1H), 10.89 (s, 1H).

EXAMPLE 41

Cyclo{-Suc[1(S)-[3-N′-(β-D-glucopiranos-1-yl)-carboxamidopropanoyl]amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—} (compound of formula I wherein h=1, g=0, R₄=-[3-N′-(β-D-glucopiranos-1-yl)carboxyamidopropanoyll]amine] and the other substituents are as defined in example 1 white the carbon atom C—R₄has configuration S)

The compound of example 40 (90 mg) was dissolved in anhydrous DMF (10 ml) under stirring and in nitrogen atmosphere, to the mixture 55 mg HBT, 25 mg EDC and 24 mg β-D-glucopiranosylamine were added.

The mixture was left stirring overnight and after evaporation of the solvent the resulting oil was treated with citric acid 10% giving a solid which was filtered, washed with water and dried. The 80 mg obtained were purified by HPLC giving 40 mg of a liophylized solid.

MS(ES+):[MH+]=842; HPLC (conditions of example 23): Rt=8.2.

1H-NMR (DMSO): δ 2.31-2.81 (m, 12H), 3.00-3.10 (m, 2H), 3.13-3.65 (m, 5H), 3.66-3.75 (m, 1H), 3.97-4.12 (m, 2H), 4.29-4.36 (m, 1H), 4.65-4.75 (m, 2H), 6.78 (d, 1H), 6.95-7.40 (m, 16H), 8.19-8.27 (m, 2H), 8.35 (d, 1H), 8.51 (d, 1H), 10.82 (s, 1H).

EXAMPLE 42

Cyclo{-Suc[1(S)-[(carboxymethyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—} TFA (compound of formula I wherein h=1, g=0, R₄=-(carboxymethyl)amino and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

a) Synthesis of cyclo{-Suc[1(S)-[(ter-butoxycarbonylmethyl)-amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}

To a solution of the compound of example 23 (130 mg) in anhydrous DMF (3 ml) DIEA (0.04 ml) and ter-butyle (0.04 ml) bromoacetate were added, the solution was stirred for 2 h and therefater the mixture was poured in KHSO₄5%. The formed solid was filtered, washed with NaHCO₃, water and dried. 100 mg of product were obtained.

HPLC (conditions of Example 23): Rt=11.3.

b) Synthesis of cyclo{-Suc[1(S)-[(carboxymethyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}.TFA

The above collected solid (90 mg) was suspended in CH₂Cl₂(5 ml) and TFA (5 ml) was added under stirring at 0° C., the mixture was stirred for 1 h at room temperature. The solution was concentrated and the obtained residue was purified by HPLC giving 40 mg of a liophylized solid.

MS(ES+):MH+]=639; HPLC (conditions of Example 23): Rt=9.4.

EXAMPLE 43

Cyclo{-Suc[1(S)-[N′-(β-D-glucopiranos-1-yl)-carboxyamidomethyl]amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—} TFA (compound of formula I wherein h=1, g=0, R₄=—[N′-(β-D-glucopiranos-1-yl)carboxyamidomethyll]amine] and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The product was obtained starting from the product of Example 42 and β-D-glucopiranosylamine according to the procedure of Example 41.

MS(ES+):[MH+]=800; HPLC (conditions of example 23): Rt=7.6.

EXAMPLE 44

cyclo{-Suc[1(S)-(chinyl)amine]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—} (compound of formula I wherein h=1, g=0, R₄=-(chinyl)amine and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

Chinic acid (50 mg) was solubilized in anhydrous DMF (10 ml) under stirring and nitrogen atmosphere, HBT (220 mg), EDC (100 mg) and the compound obtained in Example 24 (150 mg) were added. The mixture was left under stirring overnight, thereafter the solvent was evaporated and the residue treated with an aqueous solution of KHSO₄5% and extracted with etrhylacetate.

The organic phase was washed with brine, NaHCO₃5% and again brine, dried and evaporated; the obtained solid (122 mg) was purified on flash chromatography (SiO₂) eluting with chloroform/methanole:8/2; 80 mg of the desired compound were obtained.

MS(ES+):[MH+]=755; HPLC (conditions as in example 23) Rt=10.05.

EXAMPLE 45

Cyclo{-Suc[1(S)-(4-aminobutanoyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—} TFA (compound of formula I wherein h=1, g=0, R₄=-(4-aminobutanoyl)amino and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The product was obtained starting from the product of Example 23 and 4-BOC-aminobutirryc acid according to the procedure of Example 44 followed by elimination of the protecting group BOC.

MS(ES+):[MH+]=666.

EXAMPLE 46

Cyclo{-Suc[1(S)-[(1,4′)bipiperidin-1-yl]acetamido]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—} TFA (compound of formula I wherein h=1, g=0, R₄=-[(1,4′)bipiperidin-1-yl]acetamido and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The product was obtained starting from the product of Example 23 and [(1,4′)bipiperidin-1-yl]acetic acid according to the procedure of Example 44.

MS(ES+):[MH+]=789.

EXAMPLE 47

Cyclo{-Suc[1-N-(β-D-glucopiranos-1-yl)-carboxyamido]-Trp-Phe-[(R)—NH-—CH(CH₂—C₆H₅)—CH₂—NH]—} (compound of formula I wherein h=1, g=0, R₄=N-(β-D-glucopiranos-1-yl)carboxyamide and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The product was obtained starting from the product of Example 29 and β-D-glucopiranosylamine according to the procedure of Example 44.

MS(ES+):[MH+]=771.

EXAMPLE 48

Cyclo{-Suc[1(S)-[N′-(2-N-acetyl-β-D-glucopiranos-1-yl)-carboxyamido]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—} (compound of formula I wherein h=1, g=0, R₄=—N′-(2-N-acetyl-β-D-glucopiranos-1-yl)carboxyamide and the other substituents are as defined in example 1 while the carbon atom C—R₄has configuration S)

The product was obtained starting from the acid of Example 29 and 2-N-acetyl-β-D-glucopiranosylamine according to the procedure of Example 44.

MS(ES+):[MH+]=812.

Biological Activity

The compounds described in the present invention act as antagonists of the NK-2 receptor of tachykinins. The biological activity was evaluated in two in-vitro functional tests, using rabbit pulmonary artery (RPA) and hamster trachea (HT), according to the methods described by C. A. Maggi et al., Br. J. Pharmacol., 1990., 100, 588 and P. D'Orléans-Juste et al., Eur. J. Pharmacol., 1986, 125, 37. The activity of the compounds as human NK-2 receptor antagonists was assessed in a binding test using membranes of Chinese hamster ovary (CHO) cells, transfected with the NK-2 receptor of human ileum and the radioligand [¹²⁵I]NKA (Amersham, specific activity 2000 Ci/mmol) at a concentration of 100 pM in competition studies. The substances under examination were tested in a concentration range of from 0.01 nM to 10 mM. At the end of incubation (30 minutes at 20° C.), the samples were filtered on Whatman GF/B filters and employing the Brandel automatic filtration system. Radio-activity was determined by means of a gamma counter (Cobra, Canberra Packard).

The data gathered from the functional studies were expressed as pA₂(O. Arunlakshana and H. O. Schild, Br. J. Pharmacol. Chemother., 1959, 14, 48), and those of the binding studies as pKi (-log Ki calculated using the LIGAND programme: P. J. Munson et al., Anal. Biochem., 1980, 107, 220).

The compounds of the invention proved active in the tests referred to above, with pA₂values of between 5 and 9, the more powerful compounds revealing a higher affinity for the human receptor, with pKi of between 8 and 10.

List of Abbreviations Used

For the nomenclature and abbreviations of amino acids, reference is made to the recommendations of the IUPAC-IUB Joint Commission on Biochemical Nomenclaturs (Eur. J. Biochem., 1984, 138, 9); the amino acids are understood in the S configuration, if not otherwise specified.

The other abbreviations used are the following:

BOC=tert-butoxycarbonyl; Z=benzyloxycarbonyl; -Suc-=succinyl; Bzl=benzyl; PyBOP=(benzotriazol-1-yloxy)tris(pyrrolidine)phosphonium hexafluorophosphate, DIEA=N,N-diisopropylethylamine; NEt₃=triethylamine; DMF=N,N-dimethylformamide; NKA=neurochinine A; TFA=trifluoro-acetic acid; HBT=1-hydroxybenzotriazole; EDC=N-(3-dimethylaminopropyl)-N′-ethylcarbodimide hydrochloride.

The numeration of the substituents on the succinic-group is as follows:

-Suc(1-NH₂)—=—CO—CH(NH₂)—CH₂—CO—

-Suc(2-NH₂)—=—CO—CH₂—CH(NH₂)—CO—.

Claims

What is claimed is:

1. A monocyclic compound having the formula (1):

in which:

X₁, X₂, X₃, X₄, which may be the same or different from one another, is selected from the group consisting of —CONR—, —NRCO—, —OCO—, —COO—, —CH₂NR— and —NR—CH₂—, where R is H or a C_1-3alkyl or benzyl;

f, g, h, m, which may be the same or different from one another, may be 0 or 1;

R₁and R₂which may be the same or different from one another, represent the side chain of a natural amino acid selected from the group consisting of tryptophan, phenylalanine, tyrosine and histidine, or the side chain of a non-natural amino acid selected from the group consisting of;

tryptophan and phenylalanine, either mono- or di-substituted with residues selected from the group consisting of C_1-3alkyl or halo-alkyl, C_1-3alkoxyl or amino-alkoxyl, halogen, OH, NH₂and NR₁₃R₁₄, where R₁₃and R₁₄, which may be the same or different from one another, represent a hydrogen or C_1-3alkyl group;

R₃is selected from the group consisting of:

linear or branched alkyl having the formula C_nH_2n+1with n=1-5 (selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and t-butyl) cycloalkyl or alkylcycloalkyl of formula C_nH_2n−1with n=5-9 (selected from the group consisting of: cyclopentyl, cyclohexyl and methylcyclohexyl)

(CH₃)_r—Ar₁, where r=1 or 2 and where Ar₁is an aromatic group selected from the group consisting of: α-naphthyl, β-naphthyl, phenyl, indole, said Ar₁group being possibly substituted with a maximum of two residues selected from the group consisting of: C_1-3alkyl, CF₃, C_1-3alkoxyl, Cl, F, OH and NH₂;

R₄represents an L-Q group where:

L is a chemical bond or CH₂, and

Q is selected from the group consisting of:

OH, NH₂, NR₉R₁₀, OR₁₁, and where R₉and R₁₀, which may be the same or different from one another, represent a hydrogen or C_1-3alkyl group, C_1-3hydroxy alkyl, C_1-3dihydroxyaklyl, C_1-3alkyl-CONHR₁₂(wherein R₁₂is a monoglycosidic group derived from D or L pentoses or hexoses (selected from the group consisting of ribose, arabinose, glucose, galactose, fructose, glucosamine, galactosamine N-acetylglucosamine and N-acetylgalactosamine)), C_1-3alkyltetrazole, C_1-3alkyl-COOH or wherein R₉R₁₀are joined together to form with the N atom a morpholine or a piperidine ring and where R₁₁is a C_1-3alkyl chain, or a C_2-4amino-alkyl chain;

NHCOR₈wherein R₈is a cyclohexane containing from 2 to 4 OH groups, C_1-6alkyl chain containing a polar group (chosen in the group consisting of NH₂, COOH, CONHR₁₂, (wherein R₁₂is as hereabove defined) or [1,4′]bipiperidine))

COOH, COOR₁₇or CONHR₁₂, wherein R₁₂is as hereabove defined and R₁₇is as R₁₇or a group 4-nitrobenzyl

R₅, R₆, R₇are H in which the carbon atom that carries the subtituents R₃and R₇has configuration R;

wherein when R₁═R₂═a side chain of tryptophan and R₄═CH₂OH then R₃is not isopropyl.

2. A compound according to claim 1 selected from:

(a) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH]}

(b) Cyclo{-Suc-Trp-Phe-[(S)—NH—CH(CH₂C₆H₅)—CH₂—NH]}

(c) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₁₁)—CH₂—NH]}

(d) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₄(4-OCH₃))—CH₂—NH]}

(e) Cyclo{-Suc-Trp(5F)-Phe-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH]}

(f) Cyclo{-Suc-Trp(Me)-Phe-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH]}

(g) Cyclo{-Suc-Phe(3,4-Cl)-Phe-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH—]}

(h) Cyclo{-Suc-Trp-Phe(3,4-Cl)—(R)—NH—CH(CH₂C₆H₅)—CH₂—NH]}

(i) Cyclo{-Suc-Trp-Tyr-[(R)—NH—CH(CH₂C₆H₅)—CH₂—NH]}

(j) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₃-3,4-diCl)—CH₂—NH]}

(k) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂C₆H₄-4-OH)—CH₂—NH]}

(l) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂—CH₂—C₆H₅)—CH₂—NH]}

(m) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂-2-napthyl)-CH₂—NH]}

(n) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂-indol-3-yl)-CH₂—NH]}

(o) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂-5-F-indol-3-yl)-CH₂—NH]}

(p) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₄-3-F)—CH₂—NH]}

(q) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₃-3,4-diF-CH₂—NH]}

(r) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₄-4-CF₃—CH₂—NH]}

(s) Cyclo{-Suc-Trp-Phe-[(R)—NH—CH₂—CH(CH₂C₆H₅)—NH]}

(t) Cyclo{-Suc-Trp-Phe-[(S)—NH—CH₂—CH(CH₂C₆H₅)—NH]}

(u) Cyclo{-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—(CH₂)₃CO—}

(v) Cyclo{-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—N(CH₃)]—(CH₂)₃CO—}

(w) Cyclo{-Suc[1(S)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(x) Cyclo{-Suc[1(R)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(y) Cyclo{-Suc[2(S)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(z) Cyclo{-Suc[2(R)—NH₂]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(aa) Cyclo{-Suc[1(S)—NH(CH₃)]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(ab) Cyclo{-Suc[1-COO(CH₂—C₆H₄-4-NO₂)]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(ac) Cyclo{-Suc(1-COOH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]}[Cyclo {-Suc(1-COOH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]}]

(ad) Cyclo{-Suc(1-OH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]}

(ae) Cyclo{-Suc(2-COOH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]}

(af) Cyclo{-Suc(2-OH)-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]}

(ag) Cyclo{-Suc[1(S)-(2H-tetrazolyl-5-ylmethyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(ah) Cyclo{-Suc[1(S)-(morpholin-4-yl)]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(ai) Cyclo{-Suc[1(S)-N(CH₃)₂]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(aj) Cyclo{-Suc[1(S)-(piperidin-4-yl]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(ak) Cyclo{-Suc[1(S)—(N(CH₂CH₂OH)₂)]-Trp-Phe-[(R)—NH—CH(CH₂—C₅H₅)—CH₂—NH]}trifluoroacetic acid

(al) Cyclo{-Suc[1(S)—(N(CH₂CH(OH)CH₂OH)]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(am) Cyclo{-Suc[1(S)-(3-carboxypropanoyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}

(an) Cyclo{-Suc[1(S)-[3-N′-β-D-glucopyranos-1-yl)-carboxamidopropanoyl]amino]-Trp-Phe-[(R)NH—CH(CH₂—C₆H₅)—CH₂NH]—}

(ao) Cyclo{-Suc[1(S)-[(carboxymethyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(ap) Cyclo{-Suc[1(S)-[N′-β-D-glucopyranos-1-yl)-carboxyamideomethyl]amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(aq) Cyclo{-Suc[1(S)-(quinyl)amine]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}

(ar) Cyclo{-Suc[1(S)-(4-aminobutanoyl)amino]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(as) Cyclo{-Suc[1(S)-(1,4′)bipiperidin-1-yl]acetamido]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}trifluoroacetic acid

(at) Cyclo{-Suc[1-N-(β-D-glucopyranos-1-yl)-carboxyamido]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}

(au) Cyclo{-Suc[1(S)-(N′-(2-N-acetyl-β-D-glucopyranos-1-yl)-carboxyamido]-Trp-Phe-[(R)—NH—CH(CH₂—C₆H₅)—CH₂—NH]—}.

3. A composition comprising a compound of formula (I) according to claim 1 in combination with a suitable carrier or excipient.

4. Compositions according to claim 3, to be used as tachykinin antagonists.

5. Compositions according to claim 4, to be used asantagonists of the human NK-2 receptor.

6. A method of inhibiting bronchoconstriction comprising administering a compound according to claim 1 for a time and under conditions effective to antagonize NK-2 (neurokinin-2) receptors.

7. A method of inhibiting bronchoconstriction comprising administering a compound according to claim 1 to a mammal afflicted with asthma for a time and under conditions effective to antagonize NK-2 receptors.

8. A method of inhibiting bronchoconstriction comprising administering a compound according to claim 1 to a mammal afflicted with an anxiety disorder for a time and under conditions effective to antagonize NK-2 receptors.

9. A method of inhibiting bronchoconstriction comprising administering quantities of between 0.02 and 10 mg/kg of body weight of active principle consisting of a compound according to claim 1, to a patient afflicted with asthma, coughing, pulmonary irritation, intestinal spasms, spasms of the biliary tract, local spasms of the bladder and of the ureter during cystitis or kidney infections and colics for a time and under conditions effective to antagonize NK-2 receptors.

10. A mixture comprising two or more compounds according to claim 1.

11. A method of inhibiting bronchoconstriction comprising administering a compound according to claim 1 for a time and under conditions effective to antagonize NK-2 receptors.

12. A method of inhibiting bronchoconstriction comprising administering a compound according to claim 1 to a mammal in need thereof for a time and under conditions effective to antagonize NK-2 receptors.

13. A method according to claim 12 wherein said mammal is afflicted with a disorder selected from the group consisting of the bronchospastic and inflammatory component of asthma, coughing, pulmonary irritation, intestinal spasms, spasms of the biliary tract, local spasms of the bladder and of the ureter during cystitis, and kidney infections and colics.